Plasmodium falciparum, which often causes fatal cerebral malaria, especially among children, has developed resistance to the one very effective antimalarial drug chloroquine and is developing resistance to other antimalarial drugs introduced more recently such as mefloquine and halofantrin. Therefore, there is an urgent need to develop alternative drugs to counter this trend. Natural products isolated from higher plants, such as quinine and artemisinin, have provided effective drugs against malaria. In the last few decades a large number of plants, including those traditionally used, have been evaluated for their antimalarial activity. However, no new drug candidates and very few lead compounds have emerged from these efforts. Because of the ease of rapid mass production and good chemical diversity, fungi remain a good and attractive natural source for biologically active compounds. Fungi have provided the majority of agents and lead compounds currently used against bacterial infections. A few of these antibiotics are effective in combination with conventional antimalarial drugs against drug-resistant falciparum malaria. However, only very few extracts or secondary metabolites of fungi have been systematically evaluated for their antimalarial activity. Plant pathogenic fungi are known to release phytotoxic secondary metabolites, which disrupt biochemical processes in plant cells. Genomic and recent biochemical studies have shown that there are a number of plant-like metabolic pathways in the malaria parasite. Our preliminary results indicate that plant pathogenic fungi can be a good source of antimalarial compounds. The purpose of this proposal is to expand on these results and to identify antimalarial compounds from plant pathogenic fungi and their preliminary evaluation as new clinically useful antimalarial agents.